ABSTRACT Over 500,000 total knee arthroplasties (TKAs) are performed each year in the United States to alleviate pain and disability associated with knee osteoarthritis (OA), and this number is expected to grow to 3.48 million per year by the year 2030. While TKA reliably reduces pain and improves self-reported function, quadriceps strength and functional mobility remain impaired years after surgery. Long-term weakness and deficits in functional mobility likely stem from early post-operative strength loss, especially in the quadriceps muscles. Furthermore, the majority of this early quadriceps weakness occurs because of difficulty activating the muscles early after surgery. Improved rehabilitation strategies are needed to target these early impairments and prevent deficits in functional mobility. While some studies suggest that rehabilitation after TKA has no long-term benefit, emerging investigations suggest that a more aggressive rehabilitation program, using intensive progressive resistance exercise and functional strengthening, may substantially improve patient function without compromising safety. Progressive resistance exercise offers many possible advantages, including the potential to reverse muscle activation deficits, stimulate muscle hypertrophy, and improve functional performance. Early intervention with progressive exercise after TKA offers even greater benefits because preventing the decline of muscle function early after surgery is likely to be more effective than working to reverse losses months after surgery. However, there have been no prospective, randomized clinical trials examining the benefits of a progressive rehabilitation program initiated immediately after TKA. The overall aim of this investigation is to evaluate the effectiveness of a progressive resistance rehabilitation program (PROG) after TKA compared to a traditional rehabilitation program (TRAD) through a prospective, double-blinded, randomized trial. The PROG intervention will involve the early initiation of intensive rehabilitation using progressive resistance exercise and faster progression to functional strengthening exercises. The TRAD intervention represents the synthesis of previously published TKA rehabilitation programs. Functional performance and muscle muscle strength will be measured at six time points (pre-op; 1, 2, 3, 6, and 12 months after TKA) (Aims 1&2) with the primary outcome (stair climbing time) measured at 3 months. We will also determine whether PROG enhances improvements in muscle mass and central activation compared to TRAD, and explore the mechanisms by which quadriceps strength improves (Aim 3). We expect PROG will result in substantial improvements in functional mobility and strength and these improvements will specifically relate to better central activation. This study has high potential to shift current clinical practice paradigms with an immediate impact because the PROG program can be easily implemented in most clinical settings. 1